Abstract
We previously reported the discovery of a class of spirooxindoles as potent and selective small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors). We report herein our efforts to improve their pharmacokinetic properties and in vivo antitumor activity. Our efforts led to the identification of 9 (MI-888) as a potent MDM2 inhibitor (Ki = 0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy. Compound 9 is capable of achieving rapid, complete, and durable tumor regression in two types of xenograft models of human cancer with oral administration and represents the most potent and efficacious MDM2 inhibitor reported to date.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Area Under Curve
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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HCT116 Cells
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Humans
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Indoles / chemistry
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Indoles / pharmacokinetics
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Indoles / pharmacology*
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Inhibitory Concentration 50
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Kinetics
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Mice
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Microsomes / metabolism
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Molecular Structure
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Neoplasms / metabolism
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Neoplasms / pathology
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Neoplasms / prevention & control*
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Oxindoles
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Protein Binding / drug effects
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Rats
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Rats, Sprague-Dawley
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / pharmacology*
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
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Tumor Suppressor Protein p53 / metabolism
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Xenograft Model Antitumor Assays*
Substances
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Indoles
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MI-888
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Oxindoles
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Spiro Compounds
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Tumor Suppressor Protein p53
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2-oxindole
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Proto-Oncogene Proteins c-mdm2